Over the past few years, several research groups in, chiefly, England or the United States of America, have synthesized histamine H.sub.1 or H.sub.2 -receptor antagonists. The H.sub.2 -receptor antagonists are useful in treating peptic ulcers. Broadly speaking, these compounds are substituted guanidines, ##STR1## mercaptoamidines or isothioureas, ##STR2## tautomeric with the thioureas ##STR3## and ethanediamines, ##STR4## tautomeric with ##STR5## In these new H.sub.2 -receptor antagonists, the amidine or guanidine moiety usually occurs at one end of a bridging group; i.e., --CH.sub.2 --Y--(CH.sub.2).sub.2 -- where Y is S, O, NH or CH.sub.2. The other end of the bridging group has usually been an aromatic heterocycle, most frequently imidazole. The heterocyclic ring can be substituted.
The first drug recognized as a powerful H.sub.2 -receptor antagonist was a thiourea, burimamide--N-methyl-N'-(4-[4(5)-imidazolyl)]butyl)thiourea--having the following formula: ##STR6## The pharmacological properties of this compound are disclosed in The Pharmacological Basis of Therapeutics, Goodman & Gilman 5th Ed. (MacMillan Publishing Co., Inc., New York) page 612. Burimamide was developed by a group of research workers headed by Black and Durant.
A second generation of histamine H.sub.2 -receptor atagonists comprised compounds developed by Black, Durant and co-workers with a structure more or less similar to that of burimamide, but in which there was a permissible interrupting group--oxygen, sulfur or NH--in the alkyl side chain attached to the hetero ring. The most prominent of this group of compounds has been cimetidine, chemically N-cyano-N'-methyl-N"-[2-([(5-methyl-1H-imidazol-4-yl)methyl]thio)ethyl]-gu anidine, represented by the formula II below: ##STR7##
A large number of patents covering guanidines, thioureas, ethenediamines, etc., based upon several original filings (Ser. Nos. 230,451; 284,992; 385,027; 481,716; 816,420; 436,285; 542,971; 468,617; 384,993; and 385,027) have issued to Durant et al including, but not limited to, the following U.S. Pat. Nos. 3,950,333; 4,049,672; 4,022,797; 4,137,237; 4,024,271; 4,070,475; 4,154,844; 3,905,984; 4,027,026; 3,932,427; 4,018,928; 3,950,353; 4,053,473; 4,018,931; 4,069,372; 4,151,288; 4,000,296; 4,083,988; 4,129,657; 4,098,898; 4,166,856; 4,072,748; 3,971,786; 4,060,620; 3,876,647; 3,920,822; 3,897,444; 3,975,530; 4,226,874; 4,228,291; 4,230,865 and 4,221,802.
Other disclosed hetero ring systems in addition to imidazole include pyrazole, pyridine, pyrimidine, pyridazine, thiazole, isothiazole, oxazole, isoxazole, triazole, thiadiazole, benzimidazole and tetrahydroimidazo[1,5-a]pyridine, but the greatest emphasis has been on compounds having an imidazole ring system.
Patents referring to thiazole or oxazole ring systems are of particular relevance to this invention. The two basic disclosures of such compounds by the Durant group are contained in U.S. Pat. No. 3,950,333 and U.S. Pat. No. 3,950,353, both of which are continuations-in-part of Ser. No. 290,584 which was in turn a continuation-in-part of Ser. No. 230,451. In U.S. Pat. No. 3,950,333, the disclosure relating to thiazoles begins at Example 115, column 37. Thiazoles substituted with a chloro or an alkyl group are described. The thiazole nucleus is then attached at the 2- or 4-position of the thiazole ring to an alkylthioalkyl side chain terminating in an N-cyano-N'-methylguanidine. This disclosure is followed by similar disclosures for isothiazoles, oxazoles and isoxazoles. The disclosure in U.S. Pat. No. 3,950,353 relating to thiazoles begins at Example 110, column 37. Here, substantially the same thiazole nucleus is attached via a bridging group to an N-methylthiourea. A similar disclosure is present for isothiazoles, oxazoles and isoxazoles. U.S. Pat. No. 4,022,797, a division, specifically claims cyanoguanidine derivatives and U.S. Pat. No. 4,137,234, another divisional patent, specifically claims thioureas.
U.S. Pat. No. 4,000,296 to the Durant group discloses and claims a group of N-alkyl or N-arylsulfonyl-N'-alkyl-N"(heterocyclealkylthioalkyl)guanidines in which the heterocycle can be thiazole, isothiazole, oxazole or isoxazole. Alkyl, alkylaminoalkyl and alkyloxyalkyl bridging groups (connecting the heterocycle to the substituted guanidine group) are also disclosed. Substituted heterocycles belonging to any of the above classes of H.sub.2 receptor antagonists are not disclosed. U.S. Pat. No. 4,166,856, also originating with the Durant group, discloses and claims a number of imidazoles and thiazoles carrying the usual alkylthioalkyl-guanidine, -thiourea or -ethenediamine side chain, which side chain is invariably attached at the 2-position of the heterocyclic ring.
Another group of investigators under Yellin has disclosed--see U.S. Pat. Nos. 4,165,377, 4,234,735 and 4,165,378--certain novel thiazoles having a side chain such as those discussed above attached at the 4-position of the thiazole ring; i.e., an alkylthioalkyl-guanidine, -ethenediamine or -thiourea group but also bearing a guanidino group in the 2-position of the thiazole. Alkylene, alkenylene and alkyloxyalkyl bridging groups are disclosed. A representative compound is 2-guanidino-4-[2-(2-cyano-3-methylguanidino)-ethylthiomethyl]thiazole which is said to have greatly increased activity over cimetidine.
A third research group at Allen and Hanburys Ltd. has prepared compounds with a furan ring carrying the standard alkylthioalkyl (or alkyloxyalkyl or alkyl) side chain terminating in a substituted guanidine or ethenediamine group, and also having a dialkylaminoalkyl substituent attached at a second position in the furan ring--see U.S. Pat. Nos. 4,128,658 and 4,168,855. Belgian Pat. Nos. 867,105 and 867,106 disclose the corresponding aminoalkyl thiophenes and benzenes. Several of the compounds thus produced have a greater H.sub.2 receptor antagonist activity than cimetidine, the most prominent of which is ranitidine ##STR8##
U.S. Pat. No. 4,233,302 from Glaxo also discloses dialkylaminoalkyl-substituted thiophenes and furans as H.sub.2 -receptor antagonists.
Finally, a research group at Bristol-Myers have issued several U.S. patents involving different heterocycles. The first of these, U.S. Pat. No. 4,203,909, relates to furans carrying an alkylthioalkyl-guanidine (or thiourea or ethenediamine) side chain terminating in an alkynylamino group in the 2-position, and an aminoalkyl side chain in the 5-position. One of their compounds, 1-nitro-2-(2-propynylamino)-2-(2-[(5-dimethylaminomethyl-2-furyl)methylthi o]ethylamino)ethylene, is said to have 7.45 times the activity of cimetidine in a standard H.sub.2 -receptor assay. A second patent, U.S. Pat. No. 4,200,578, covers broadly thiazoles substituted with an alkylthioalkylguanidine (or thiourea or ethenediamine) side chain, and again carrying an obligatory alkynyl group in the terminal portion. Other permissible substituents in the thiazole ring include alkyl, guanidino or aminoalkyl. Despite the broad disclosure, the actual working examples (compounds actually prepared) in U.S. Pat. No. 4,200,578 are limited to thiazoles carrying the alkylthioalkylguanidine, etc. side chain in the 2-position of the thiazole ring except for a few compounds in which the side chain is carried in the 4-position, but in which there is an obligatory guanidino group in the 2-position. Synthetic Schemes I through VIII of the patent are suitable only for preparing 2-substituted thiazoles. Example 17 discloses thiazoles with a dimethylaminomethyl group substituted in the 4-position and the methylthioethyl side chain in the 2-position. The side chain terminates in a N-alkynyl 2-nitro-1,1-ethenediamine group. The compound, 1-nitro-2-(2-propynylamino)-2-( 2-[(4-dimethylaminomethylthiazol-2-yl)methylthio]ethylamino)ethylene, also named as N-(2-propynyl)-N-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl 2-nitro-1,1-ethenediamine, is specifically disclosed.
U.S. Pat. No. 4,200,760 has a similar disclosure of an ethenediamine carrying a alkynylamine group attached by a bridging group to an imidazole ring. Pyridine is the heterocycle in U.S. Pat. No. 4,250,316. However, a recent Bristol-Myers Belgian Pat. No. 885,089, published Mar. 4, 1981, same as U.K. Pat. No. 2,067,987, discloses a group of H.sub.2 -receptor antagonists among which are included compounds of the formula ##STR9## One compound specifically disclosed is prepared from 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine--See Example 22, part E page 72 et seq.
Many of the above cited patents disclose alkenyl groups as permissible substituents on one guanidine nitrogen; ie., U.S. Pat. No. 4,098,898 and 4,166,856 disclose the allyl group.
To summarize, thiazoles in which there is a 4-alkylthioalkylguanidine (or thiourea or ethenediamine) side chain are known wherein the thiazole group can be substituted in the 2- or 5-position with guanidino, methyl, chloro and aminoalkyl. Generic disclosures of thiazoles substituted with an aminoalkyl group at one position in the thiazole ring are in the art. These thiazoles have, at a second position in the thiazole ring, a bridging alkylthioalkyl, alkylene, alkenylene or alkyloxyalkyl group terminating in a substituted guanidine group, which carries an N-alkynyl or N-alkenyl group. N-(2-Propynyl)-N'-2-(4-dimethylaminomethyl-2-thiazolylmethylthio)ethyl-2-n itro-1,1-ethenediamine is specifically disclosed in Algieri et al, U.S. Pat. No. 4,200,574, Example 17.